P1052: A REAL-WORLD STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SELINEXOR IN COMBINATION WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS
Authors: Minghui Duan, Lan MA, Qiuling Wu, Hong Liang, Wei Wang, Shaoling Wu, Lijun Mu, Hai Lin, Hebing Zhou, Hongxia Shi, Hongmei Jing
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Selinexor (SEL) is a first-in-class, oral selective inhibitor of nuclear export agent that binds the karyopherin protein exportin 1 (XPO1). Myelofibrosis (MF) is a hematopoietic stem cell neoplasm associated with constitutive activation of JAK/STAT signaling pathway. Preclinical studies showed SEL decreased viable cells and colony formation both in newly diagnosed and Ruxolitinib(RUX)-exposed MF cells. A phase I study reported, with SEL plus RUX in treatment-Naïve MF, 92% patients(pts) achieved SVR35, 69% had symptom response and 65% had stable or improved Hgb levels. Besides, ESSENTIAL trial showed SEL’s sustained spleen responses as a single agent in JAKi refractory MF. Aims: To evaluate the efficacy and safety of SEL plus RUX in MF patients. Methods: This is a prospective, investigator-initiated, multi-center, cohort study examining SEL plus RUX regimen in MF patients in real-world setting. MF Patients were given SEL plus RUX (dosage per investigator judgement). Primary efficacy endpoint was spleen response assessed by palpation or CT/MRI scan per IWG-MRT and ELN response criteria. Key secondary endpoints included anemia response, symptom response defined as symptom resolution or alleviation according to TSS or physician’s judgement, and safety. Results: As of Feb 2023, 20 pts had received at least one dose of oral weekly SEL (20mg, n=1; 40mg, n=7; 60mg, n=12) with RUX twice daily as per investigator judgement. Median age was 66 years old (range 43-75). 13 pts had primary MF, 2 had post-PV MF, and 5 had post-ET MF. 11/14 pts (79%) had peripheral blood blasts 1-4% (6 pts unknown). Median time from MF diagnosis to study enrollment was 3 years (rang 1-33) and median duration of prior RUX treatment was 22 months (0 to 77 months), including 1 RUX naïve and 19 suboptimal responses (n=5) or intolerable (n=14) pts. JAK2, CALR and MPL mutations were present in 14 (70%), 2 (10%) and 1 (5%) pts respectively. 17 pts had splenomegaly, and 4 pts had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was int-2 (n=16), high risk (n=1) and unknown (n=3). Median treatment duration was 154 days (range 26-372). Of patients evaluable for spleen response, 6/13 (46%) achieved SVR35 or equally spleen reduction assessed by palpation. 15 pts with available data and received at least 8 weeks of treatment were evaluated for symptom response, 13/15 (87%) had symptom alleviation (10 pts achieved≥50% reduction in TSS or significant symptom response assessed by physician, of which 1 achieved symptom resolution). 15/16 (94%) PRBC transfusion-independent pts maintained stable hemoglobin (Hgb, ± 20g/L; n=10, 63%) or improved Hgb levels (>20g/L increase; n=5, 31%) at the last follow up. 3/4 (75%) PRBC transfusion-dependent pts became transfusion independent(n=1) or had reduced PRBC transfusion frequency (n=2). 11 pts (55%) discontinued SEL. Reasons for treatment discontinuation are death in 5 pts (2 from covid-19, 1 sepsis and 2 unknown), participate in clinical trial in 1 pt, unsatisfactory response in 2 pts, transplantation in 1 pt, and toxicity in 2 pts. The most common treatment-emergent adverse events (TEAEs) were nausea (11/20, 55%), vomiting (8/20, 40%), decreased appetite (6/20, 30%) and anemia (5/20, 25%). The most common Grade 3 TEAEs were anemia and thrombocytopenia. Conclusion: In this preliminary analysis, the combination of SEL and RUX shows promising clinical activity to date in pts with myelofibrosis. The combination has a manageable side effect profile to date. Keywords: Real world data, Myeloproliferative disorder, Myelofibrosis, Ruxolitinib